Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease.
Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease.
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DOI：
10.1158/1078-0432.ccr-08-2332
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Mukhtar H
中科院分区：
文献类型：
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作者：
Adhami VM;Siddiqui IA;Sarfaraz S;Khwaja SI;Hafeez BB;Ahmad N;Mukhtar H
我们之前已经证明，在纯化学预防的环境下，口服绿茶多酚(GTP)给转基因小鼠前列腺癌可以显著抑制前列腺癌的发展。为了将这种情况转化为人类情况，本研究旨在确定前列腺癌最容易受到GTP化学预防干预的阶段。在转基因小鼠前列腺癌模型中，分别在6周(组1，正常前列腺)、12周(组2，前列腺上皮内瘤变)、(C)18周(组3，高分化腺癌)和(B)28周(组4，中分化腺癌)的不同年龄段开始注射GTP(含0.1%饮用水)。在32周龄时，通过磁共振成像、超声和前列腺重量以及血清胰岛素样生长因子(IGF)-I/IGF结合蛋白-3和IGF信号转导对动物亚群进行评估。无瘤生存期分别延长至38周(P<；0.001)、31周(P<；0.01)和24周(P<；0.05)，而饮水对照组为19周。中位预期寿命：第1组为68周，第2组为63周，第3组为56周，第4组为51周，而对照组为42周。IGF-I及其下游靶点，包括磷脂酰肌醇3-激酶、PAKT和磷酸化细胞外信号调节激酶，只有在前列腺上皮内瘤变常见的早期开始干预时才被显著抑制。我们的研究表明，GTP的化学预防潜力随着疾病的进展而降低，并强调了设计适当的化学预防临床试验的必要性。
We have shown previously that oral feeding of green tea polyphenols (GTP) to transgenic adenocarcinoma of the mouse prostate mice in a purely chemopreventive setting significantly inhibits prostate cancer development. To translate this to a human situation, the present study was designed to identify the stage of prostate cancer that is most vulnerable to chemopreventive intervention by GTP. GTP infusion (0.1% in drinking water) to transgenic adenocarcinoma of the mouse prostate was initiated at ages representing different stage of the disease: (a) 6 weeks (group 1, normal prostate), (b) 12 weeks (group 2, prostatic intraepithelial neoplasia), (c) 18 weeks (group 3, well-differentiated adenocarcinoma), and (b) 28 weeks (group 4, moderately differentiated adenocarcinoma). At age 32 weeks, subsets of animals were evaluated by magnetic resonance imaging, ultrasound, and prostate weight and for serum insulin-like growth factor (IGF)-I/IGF binding protein-3 and IGF signaling. Tumor-free survival was extended to 38 weeks (P < 0.001) in group 1, 31 weeks (P < 0.01) in group 2, and 24 weeks (P < 0.05) in group 3 compared with 19 weeks in water-fed controls. Median life expectancy was 68 weeks in group 1, 63 weeks in group 2, 56 weeks in group 3, and 51 weeks in group 4 compared with 42 weeks in the control mice. IGF-I and its downstream targets including phosphatidylinositol 3-kinase, pAkt, and phosphorylated extracellular signal-regulated kinase were significantly inhibited only when intervention was initiated early when prostatic intraepithelial neoplasia lesions were common. Our studies indicate that chemopreventive potential of GTP decreases with advancing stage of the disease and underscore the need to design appropriate chemoprevention clinical trails.